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United States Patent Ofitice 3,026,321 Patented Mar. 20, 1962 3,026,321NEW SUBSTlTUTED 2,6-DIKETOPIPERAZINE AND ITS MANUFACTURE David K. dc.lough, Heemstede, Adriaan Kraaijeveld, Oegstgeest, and Geertruida C.van Leeuwen and Josephus F. Michels, Amsterdam, Netherlands, assignorsto N.V. Nederlandsche Combinatie voor Chemische Industrie, Amsterdam,Netherlands, a company of the Netherlands N Drawing. Filed Sept. 9,1959, Ser. No. 838,852

4 Claims. (Cl. 260268) This invention concerns a new substituted2,6-diketopiperazine and its manufacture.

This is a continuation-in-part of our application Serial Number 796,772,filed March 3, 1959, and now abandoned.

It has been found that the compound 4-[5-(3,4-dimethoxyphenyl)ethyl] 2,6diketopiperazine is valuable owing to its specific depressant activityon the central nervous system in test animals as Well as in humantherapy. Regarding the activity in test animals the compound differsfrom the general depressants by specifically inhibiting conditionedresponses. In accordance with this observation a pronouncedtranquillizing activity was noted in human patients with anxiety states.

Further it has been found that the compound according to the inventionmay be prepared by heating B-(3,4-dimethoxyphenyl)ethyliminodiaceticacid with a slight excess of urea at a temperature above the meltingpoint of the mixture, for example to temperatures within the range offrom 150 C. to 210 0, preferably of from 170 C. to 190 C. The amount ofurea used may vary, but for best results the amount is kept within therange of from 1 to 1.2 m-oles, preferably about 1.1 moles of urea permole of the acid.

The starting material for this method may be prepared by heating{3-(3,4-dimethoxyphenyl)ethylamine with at least a double molecularproportion of a monohalogenacetic acid, preferably monochloracetic acid,to temperatures between 40 C. and 60 C., preferably between 45 C. and 50C., for from 5 to 30 hours, preferably to 20 hours, in the presence of asufficient amount of an acid binding agent. As a hydrogen halide bindingagent may be used an alkali metal hydroxide, an alkali metal carbonateor an alkali metal bicarbonate. Preferably sodium hydroxide is used.

The following examples serve to illustrate the invention. Thetemperatures are given in degrees centigrade. The melting points areuncorrected.

Example 1 A solution of 24.1 grams of monochloracetic acid in 40 cc. ofwater is added to 25.3 grams of sodium hydroxide in 80 cc. of Water at atemperature below 30. Subsequently 27.7 grams ofp-(3,4-dimethoxyphenyl)- ethyl amine hydrochloride are added and 20 cc.of ethanol to keep the free amine in solution. The reaction mixture isheated to 45 50 and kept at that temperature overnight. Thereafterconcentrated hydrochloric acid is added until a pH of 23 is reached andthe mixture is allowed to cool. The precipitate is filtered and dried,melting at 201-203 after recrystallization from water. By adding freshmonochloracetic acid and sodium hydroxide to the residue and againheating overnight at 45 50 another crop of crystals may be obtained inthe same Way.

17.2 grams of this fl-(3,4-dimethoxyphenyl)ethyliminodiacetic acid aremelted together with 3.8 grams of urea at a temperature of l50160, andthereafter the temperature is raised to 170-190. After the firstvigorous reaction has subsided, the reaction mixture is heated at thesame temperature for another 30 minutes. The mixture is allowed to cooland the residue obtained is recrystallized from ethanol or frommethylethylketo-ne. It is also possible to sublimate the reactionproduct. The sublimate is then recrystallized in the same way. A pure4-[fl-( 3,4 dimethoxyphenyl)ethyl]-2,6 diketo-piperazine is obtained,melting at 128l29.

Example 2 A solution of 20.9 grams of monochlorace-tic acid in 35 cc. ofwater is added to 22.6 grams of sodium hydroxide in cc. of water at atemperature below 30. Subsequently 24 grams of 9-(3,4dimethoxyphenyl)ethylamine hydrochloride in 25 cc. of alcohol are added.The reaction mixture is heated to 50 and kept at that temperatureovernight. Monochloracetic acid and sodium hydroxide are again added andthe mixture is again heated overnight to 50. After evaporation of thealcohol a solution of barium chloride in water is added and the mixtureis heated for half an hour on the steam bath. After cooling theprecipitate is filtered and Washed with hot water. The barium salt ofthe iminO-acid is converted into the free acid by adding the calculatedamount of sulphuric acid While boiling and stirring the mixture. Thebarium sulphate obtained is filtered by suction and washed carefullywith boiling Water. The filtrate is evaporated and the residuerecrystallized from a mixture of water and alcohol. The acid melts at201 203.

9 grams of this B-(3,4-dimethoxyphenyl)ethyliminodiacetic acid and 2grams of urea are melted together. The mixture is heated to 190-200while the gases are removed under reduced pressure. After 35 minutes themixture is allowed to cool to some extent and then dissolved in alcohol.By cooling this solution the 4-[fl-(3,4- dimethoxyphenyl)-ethyl]-2,6diketopiperazine is isolated with a melting point of 128l29.

What is claimed is:

l. The compound 4[;3-(3,4 dimethoxyphenyl)ethyl]- 2,6-diketopiperazine.

2. The method of producing4-[;8-(3,4-dimethoxyphenyl)-ethyl]-2,6-diektopiperazine, comprisingheating 543,4- dimethoxyphenyl)ethyliminodiacetic acid with urea in aproportion of from 1 to 1.2 moles of urea per mole of said acid to atemperature of from C. to about 210 C. for a period of at least about 30minutes.

3. The method of producing 4-[ 3-(3,4-dimethoxyphenyl)ethyl] 2,6diketopiperazine comprising the steps of heatingB-(3,4-dimethoxyphenyl)ethylamine with at least a double molecularproportion of a monohalogen-acetic acid at temperatures between 40 C.and 60 C. for from 5 to 30 hours in the presence of a hydrogen halidebinding agent selected from the group consisting of alkali metalhydroxides, alkali metal carbonates and alkali metal bicarbonates, toyield fl-(3,4-dimethoxyphenyl)ethyliminodiacetic acid and heating saidiminodiacetic acid with urea in a proportion of from 1 to 1.2 moles ofurea per mole of said irninodiacetic acid to a temperature of from 150C. to about 210 C. for a period of at least about acid to a temperatureof from 170 C. to 190 C. for a 30 minutes, period of at least about 30minutes.

D 1 g gf PrPduCi1 1g f i References Cited in the file of this patent yet y] 1 etoplperazme comprlsmg t e steps 0 heatingfi-(3,4-dimethoxypheny1)ethylamine with at least 5 UNITED STATES PATENTSa double molecular proportion of a monochloracetic acid 2,762,804 SafirP 1955 at temperatures between 45 C. and 50 C. for from 10 2 52 3 2Safir Sept 11, 1955 to 20 hours in the presence of sodium hydroxide toyield 7 Weston et a1 1958 fi-(3,4-dimethoxypheny1)ethylirninodiaceticacid and heat- OTHER REFERENCES ing said iminodiacetic acid with urea ina proportion of Dubsky: Berichte Deutsche Chemische Gesellschaft, about1.1 moles of urea per mole of said iminodiacetic v01. 54, pages2659-2667 (1921).

1. THE COMPOUND 4-(B-(3,4-DIMETHOXYPHENYL)ETHYL)2,6-DIKETOPIPERAZINE.